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  Systems and methods for the delivery of corticosteroidsUSPTO Application #: 20070249572Title: Systems and methods for the delivery of corticosteroids Abstract: The present invention relates to methods and systems for the delivery of a corticosteroid comprising (1) an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer and (2) an inhalable nebulizer, wherein the delivery of the aqueous mixture comprising the corticosteroid by the nebulizer results in an enhanced pharmacokinetic profile of the corticosteroid as compared to conventional inhalable therapies and/or increase lung deposition. (end of abstract) Agent: Wilson Sonsini Goodrich & Rosati - Palo Alto, CA, US Inventor: Malcolm Hill USPTO Applicaton #: 20070249572 - Class: 514178000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Cyclopentanohydrophenanthrene Ring System Doai, Oxygen Double Bonded To A Ring Carbon Of The Cyclopentanohydrophenanthrene Ring System, Oxygen Single Bonded To A Ring Carbon Of The Cyclopentanohydrophenanthrene Ring System The Patent Description & Claims data below is from USPTO Patent Application 20070249572. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE [0001] This application is a continuation-in-part application of U.S. patent application Ser. No. (not yet assigned) filed Dec. 19, 2006 and identified by Attorney Docket No. 31622-720.202, which is incorporated herein by reference in its entirety and to which application we claim priority under 35 U.S.C. .sctn. 120. This application also claims priority under 35 U.S.C. .sctn. 119(e) to each of U.S. Provisional Application Ser. Nos. 60/752,735, filed Dec. 20, 2005; 60/773,998 and 60/773,999, both filed Feb. 15, 2006; and 60/820,092, 60/820,094, 60/820,096, all filed Jul. 21, 2006. FIELD OF THE INVENTION [0002] The present invention relates to methods and systems for the delivery of a corticosteroid comprising (1) an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer and (2) an inhalable nebulizer, wherein the delivery of the aqueous mixture comprising the corticosteroid by the nebulizer results in an enhanced pharmacokinetic profile of the corticosteroid as compared to conventional inhalable therapies and/or increased lung deposition. BACKGROUND OF THE INVENTION [0003] Inhaled corticosteroids are fundamental to the long-term management of persistent asthma and are recommended by national guidelines for therapy of young children diagnosed with asthma. Numerous clinical trials support their efficacy and relative safety for children. In addition, it is believed that early corticosteroid intervention can play a critical role in the reduction of permanent lung damage and alter the chronic, progressive nature of the disease. [0004] The use of inhaled corticosteroids in the treatment of asthma provides significant benefit due to the direct delivery to the site of action, the lung (as used herein, "lung" refers to either or both the right and left lung organs). The goal of inhaled corticosteroid therapy is to provide localized delivery of the corticosteroid with immediate drug activity at the site of action. It is known that inhaled corticosteroids are well absorbed from the lungs. In fact, it can be assumed that substantially all of the drug available at the receptor site in the lungs will be absorbed. However, it is also known that current methods and formulations result in a greater part of an inhaled corticosteroid dose being swallowed and becoming available for oral absorption. Thus, due to the particular method or system employed, some corticosteroids are more likely to be deposited in the mouth and throat than the lungs, and may cause adverse effects. For the portion of the inhaled corticosteroid dose delivered orally, bioavailability depends upon absorption from the GI tract and the extent of first pass metabolism in the liver. Since this oral component of corticosteroid drug delivery does not provide any beneficial therapeutic effect and increases the risk of systemic side effects, it is desirable for the oral bioavailability of inhaled corticosteroid to be relatively low. Thus, for inhaled corticosteroids, high pulmonary availability is more important than high oral bioavailability because the lung is the target organ. [0005] As such, a method or system of delivery that provides a corticosteroid with high pulmonary availability has greater potential to exert positive effects in the lung. The ideal system of providing inhaled corticosteroids would provide minimum oral delivery and reduced administration times thereby reducing the likelihood of systemic adverse effects. [0006] Unfortunately, however, the delivery of a corticosteroid via inhalation often results in deposition of the corticosteroid in sections distinct from the respiratory tract, e.g., mouth, throat, and esophagus. Generally, the smaller the particle size of the corticosteroid, the longer the particle will remain suspended in air and the farther down the respiratory tract the drug can be delivered. Corticosteroids are delivered by inhalation using nebulizers, metered dose inhalers, or dry powder inhalers. The principle advantage of nebulizers over other methods of pulmonary delivery of a corticosteroid is that nebulizers can more efficiently deliver higher doses of medication compared to other methods. The main concerns about nebulizers, however, are the increased cost, reduced portability, and the inconvenience of needing to prepare medication beforehand and the increased time requirement for administering a treatment. Thus, a method of improving the delivery of drugs, such as corticosteroids by nebulization, is desired. [0007] Both particle size and formulation influence the efficacy of an inhaled corticosteroid. The formulation of a drug has a significant impact on the delivery of that drug to the lungs, and therefore its efficacy. Additionally, it is believed that the most important considerations in the delivery of drug to the lung are the aerosol vehicle and the size of the particles delivered. [0008] The inhalation of drug particles as opposed to dissolved drug is known to be disadvantageous. Brain et al. (Bronchial Asthma, 2nd Ed. (Ed. E. B. Weis et al., Little Brown & Co. (1985), pp. 594-603) report that less soluble particles that deposit on the mucous blanket covering pulmonary airways and the nasal passages are moved toward the pharynx by the cilia. Such particles include larger drug particles which are deposited in the upper respiratory tract. Mucus, cells and debris coming from the nasal cavities and the lungs meet at the pharynx, mix with saliva, and enter the gastrointestinal tract upon being swallowed. Reportedly, by this mechanism, particles are removed from the lungs with half-times of minutes to hours. Accordingly, there is little time for solubilization of slowly dissolving drugs, including corticosteroids, e.g., budesonide. In contrast, particles deposited in the non-ciliated compartments, such as the alveoli, have much longer residence times. Since it is difficult to generate very small particles of corticosteroids for deep lung deposition, much of the inhaled suspension would likely be found in the upper to middle respiratory tract. However, it is much easier to generate small droplets from a solution than it is from a suspension of solids. [0009] Budesonide (R,S)-ll.beta.,16.alpha.,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde, (C.sub.25H.sub.34O.sub.6; MW: 430.5) is employed in particular for the treatment of bronchial disorders. Budesonide is a racemate consisting of a mixture of the two diastereomers 22R and 22S and is provided commercially as a mixture of the two isomers (22R and 22S). It acts as an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity. Administration of budesonide is indicated for maintenance treatment of asthma and as prophylactic therapy in children. [0010] Because of its lipophilicity, budesonide, as well as other lipophilic corticosteroids, is virtually insoluble in water but is readily soluble in alcohols. An adequate amount of active substance can be dissolved by the use of solubilizers such as organic, water-soluble alcohols. However, the solutions obtained in this way generally limited stability for pharmaceutical use because large amounts of the active substance may decompose within a short time. [0011] Commercial formulations of budesonide are sold by AstraZeneca LP (Wilmington, Del.) under the trademarks Entocort.RTM. EC, Pulmicort Respules.RTM., Rhinocort.RTM. Aqua, Rhinocort.RTM. Nasal Inhaler and Pulmicort.RTM. Turbuhaler, and under its generic name. Pulmicort Respules.RTM., which is a sterile aqueous suspension of micronized budesonide, is administered by inhalation using a nebulizer, in particular a compressed air driven jet nebulizer. Rhinocort.RTM. Nasal Inhaler is a metered-dose pressurized aerosol unit containing a suspension of micronized budesonide in a mixture of propellants. Rhinocort.RTM. Aqua is an unscented metered-dose manual-pump spray formulation containing a suspension of micronized budesonide in an aqueous medium. In addition, suspension formulations of budesonide have a propensity to rapidly form coarse flocs upon dispersion and re-dispersion which may deleteriously affect dosage reproducibility. There is also a tendency for budesonide to deposit from suspension onto the walls of the container. [0012] Accordingly, there is a need for systems and methods for delivering a non-suspension formulation comprising a corticosteroid by nebulization. However, even in light of this need, the Pulmicort Respule.RTM. suspension is the only currently approved therapy for the treatment of pediatric asthma with budesonide via inhalation therapy. In addition, the availability of compositions, methods, and systems for corticosteroids other than budesonide is likewise needed. Thus, it would be a significant advancement to the field of corticosteroid inhalation therapy to provide a method or system which provides enhanced pharmacokinetic profiles of the delivered corticosteroid as compared to the pharmacokinetic profile of suspension unit dose formulations containing a corticosteroid, and/or increased lung deposition. SUMMARY OF THE INVENTION [0013] In certain embodiments, the present invention provides an inhalable composition comprising about 250 .mu.g or less of a single corticosteroid, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a device, the composition achieves a rate of increasing concentration of the corticosteroid inside the device of about 5 .mu.g/ml per minute or less over administration of the corticosteroid through the device and wherein the composition is substantially free of active pharmaceutical agents other than the corticosteroid. [0014] In certain embodiments, the present invention provides an inhalable composition wherein the composition achieves a rate of increasing concentration of the corticosteroid inside the device of about 5 .mu.g/ml per minute or less over the first three minutes of administration. [0015] In certain embodiments, the present invention provides an inhalable composition, wherein the composition achieves a rate of increasing concentration of the corticosteroid inside the device of about 3.5 .mu.g/ml per minute or less over the first 3 minutes of administration. [0016] In certain embodiments, the present invention provides an inhalable composition wherein the composition achieves a rate of increase in concentration of the corticosteroid inside the device of about 5% per minute or less over the first 3 minutes of administration. [0017] In certain embodiments, the present invention provides an inhalable composition wherein the solvent comprises water. [0018] In certain embodiments, the present invention provides an inhalable composition wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-.alpha.-CD, SBE-.beta.-CD, SBE1-.beta.-CD, SBE4-.beta.-CD, SBE7-.beta.-CD, SBE-.gamma.-CD, dimethyl .beta.-CD, hydroxypropyl-.beta.-cyclodextrin, 2-HP-.beta.-CD, hydroxyethyl-.beta.-cyclodextrin, hydroxypropyl-.gamma.-cyclodextrin, hydroxyethyl-.gamma.-cyclodextrin, dihydroxypropyl-.beta.-cyclodextrin, glucosyl-.alpha.-cyclodextrin, glucosyl-.beta.-cyclodextrin, diglucosyl-.beta.-cyclodextrin, maltosyl-.alpha.-cyclodextrin, maltosyl-.beta.-cyclodextrin, maltosyl-.gamma.-cyclodextrin, maltotriosyl-.beta.-cyclodextrin, maltotriosyl-.gamma.-cyclodextrin, dimaltosyl-.beta.-cyclodextrin, methyl-.beta.-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain embodiments, the solubility enhancer comprises SBE7-.beta.-CD. [0019] In certain embodiments, the present invention provides an inhalable composition wherein the device is a nebulizer. In certain embodiments, the device is a Pari eFlow nebulizer. [0020] In certain embodiments, the present invention provides an inhalable composition wherein the composition comprises the corticosteroid in a nominal dosage of about 60 .mu.g. Continue reading... Full patent description for Systems and methods for the delivery of corticosteroids Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Systems and methods for the delivery of corticosteroids patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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